1

Commentary:

Overcoming the blood-brain barrier with an implantable

ultrasound device

Adam M. Sonabend, MD & Roger Stupp, MD

Malnati Brain Tumor Institute

Lurie Comprehensive Cancer Center and

Departments of Neurological Surgery and Neurology

Northwestern University Feinberg School of Medicine

Chicago, IL 60611 / USA

Correspondence to:

Roger Stupp, MD

Malnati Brain Tumor Institute, Lurie Compr. Cancer Center

Departments of Neurological Surgery, Neurology and Division of Hematology/Oncology

Northwestern University Feinberg School of Medicine

676 N. Saint Clair St

Suite 2210

Chicago, IL 60611

roger.stupp@northwestern.edu

Running title: Overcoming the blood-brain barrier with ultrasound

Disclosure: A. M. Sonabend is an inventor of a patent for combining ultrasound with

albumin-bound paclitaxel for treating brain tumors (patent 47460-60). No potential conflicts

of interest were disclosed by the other author.

Research. on November 9, 2020. © 2019 American Association for Cancerclincancerres.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 10, 2019; DOI: 10.1158/1078-0432.CCR-19-0932

2

Funding: A. M. Sonabend is supported by the NIH Director’s HRHR Program

(5DP5OD021356-04), and Developmental funds from The Robert H Lurie NCI Cancer

Center Support Grant no. P30CA060553. A. M. Sonabend and Roger Stupp are supported

by a Developmental Project Award from the Northwestern University SPORE for

Translational Approaches to Brain Cancer (P50CA221747; PI: Maciej Lesniak).

Summary:

Ultrasound-based blood-brain-barrier disruption enhances drug delivery. To bypass the

human skull, an implantable ultrasound emitter was developed, proven safe and feasible in a

first-in-human trial. Next development steps aim for larger field of disruption, quantification

drug level, use of various drugs, and ultimately a pivotal trial demonstrating improved

outcome.

Main Text:

In this issue of CLINICAL CANCER RESEARCH, Idbaih and colleagues report on their

phase 1 trial of opening the blood-brain barrier with the use of an implantable ultrasound [1].

Infiltrative gliomas and glioblastoma in particular, remain an incurable disease. As numerous

novel therapeutic approaches have failed in controlled clinical trials, temozolomide remains

the first-line drug in the treatment of these tumors, which is in part explained by its good

penetration across the blood-brain barrier (BBB). Indeed, the BBB is a major impediment to

drug therapy of brain tumors, and thus, the technology evaluated on this trial overcomes

such limitation.

Pulsed-ultrasound, when used in combination with intravenous injection of microbubbles,

transiently disrupts the BBB. This technology has been around for some time, and shown to

enhance delivery of anti-tumoral agents to the brain in a multitude of pre-clinical models.

However, translation of this approach into patients requires the ultrasonic waves to either

penetrate or bypass the relatively thick human skull. Our French colleagues take it to a new

level by implanting the ultrasound emitter into a window on the patients’ skull, thus

overcoming the intrinsic resistance of the skull when using conventional external systems.

This system has allowed easy and repeat opening of the BBB. The ultrasound emitter

activates microbubbles that are simultaneously administered intravenously. By this means,

the BBB is mechanically disrupted, and diffusion of larger and polar molecules into the brain

Research. on November 9, 2020. © 2019 American Association for Cancerclincancerres.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 10, 2019; DOI: 10.1158/1078-0432.CCR-19-0932

3

becomes feasible. The BBB opening is reversible and lasts for several hours after the

sonication.

Here Idbaih and colleagues have successfully treated 19 patients with BBB disruption using

the implantable ultrasound emitter, and concomitant administration of the cytotoxic

chemotherapy agent carboplatin [1, 2]. They visualize the opening of the blood brain barrier

as temporary extravasation of gadolinium on magnetic resonance imaging performed

immediately after each sonication. They report “successful” BBB opening in 52 of 65

sonication sessions. Overall, treatment-emergent toxicity was mild-moderate and related to

the known toxicity of the chemotherapy agent used. No hemorrhage or severe neurological

symptoms were observed. Two occurrences of transient grade IV edema were attributed to

the ultrasound and BBB opening, one event occurring within hours of sonication, the other

only on day 15 and possibly related to tumor progression.

Idbaih and colleagues chose carboplatin as the chemotherapy agent for this first in human

trial. The small number of patients does not allow for any conclusions regarding treatment

efficacy, nevertheless, the trend for improved patient outcome in patients with successful

opening of the BBB is encouraging. The delivery of other and potentially more effective

agents will certainly have to be investigated in future trials.

Ultrasound based BBB-disruption is an emergent technology actively being investigated in

gliomas in at least 5 separate clinical trials currently registered on clinicaltrials.gov (table 1).

This approach to enhancing drug delivery could have an important impact on brain tumor

therapy by making it possible to achieve efficacious delivery of potent drugs that otherwise

would not penetrate across the BBB.

The concept of implantable ultrasound emitters is intriguing. Given that the ultrasonic waves

do not penetrate across the bone, this system avoids variability of acoustic transmission

secondary to irregularities in skull thickness, or metal plates that are commonly used to

fixate the bone after a craniotomy in these patients. Implantable ultrasound devices can

generate reproducible sound waves targeted to the brain tissue infiltrated by tumor cells.

Therefore, this technology does not require complex MRI guidance or feedback systems to

modulate the high-energy pulses that are required for BBB-disruption by transcranial

ultrasound technologies.(3-5) Thus with this approach, BBB disruption promises to be simple

and accessible, allowing for repetitive treatments in an outpatient setting. Potent larger

molecules may be delivered to infiltrating brain tumor cells that are normally protected by the

BBB. In this paper the principle feasibility of this technology has been nicely demonstrated.

Yet, between the proof-of-principle and the broad adaptation of this emergent technology,

there will be several challenges to be overcome (Figure). Quantification of drug levels in the

Research. on November 9, 2020. © 2019 American Association for Cancerclincancerres.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 10, 2019; DOI: 10.1158/1078-0432.CCR-19-0932

4

tumor and in the adjacent infiltrated human brain tissue would be informative. Whereas pre-

clinical studies demonstrate effective opening of the BBB, there are several species

differences that limit the extrapolation and complicate implementation of these approaches

in humans. The acoustic pressures and the dosing regimens used in patients cannot be

directly tested in small animals. Another requirement is expanding the volume of BBB

disruption. For the current study, only one single ultrasound emitter was implanted, thus

providing BBB disruption to only a small field of sonication. However, as almost all primary

brain tumors are a diffusely infiltrating diseases with tumor cells migrating well beyond the

initial visible tumor margin, larger volume BBB disruption will be important in order to

achieve a clinical impact. A second-generation implantable device with 9 ultrasound emitters

is currently undergoing clinical testing by the same group of investigators. And lastly, before

broad adoption of ultrasound-based BBB disruption for drug delivery in general, the clinical

value will need to be demonstrated for several therapeutic agents. The choice of carboplatin,

an agent that is occasionally used for salvage therapy in recurrent glioma has been used for

this first-in-human clinical trial, largely because the agent is established with a well-known

toxicity profile. The experience with carboplatin may be extrapolated to other potentially

more active antitumor agents. It will be important to establish streamlined regulatory

pathways that allow the concomitant use of various chemotherapy agents and drugs without

repeating every clinical experiment. Sonication parameters can be obtained and

extrapolated from prior trials. For many established and novel drugs with promising

preclinical activity the limited penetration and distribution beyond the BBB has been an

important cause of failure. Ultrasound-based opening of the BBB provides an opportunity for

adequate regional drug delivery with limited local or systemic toxicity. And lastly, it remains

to be evaluated whether such a technology can also enhance drug delivery for other

neurological diseases. We commend Idbaih and collaborators for this innovative technology

which opens both the BBB, as well as exciting therapeutic possibilities for gliomas, a disease

beyond reach for most drugs.

Research. on November 9, 2020. © 2019 American Association for Cancerclincancerres.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 10, 2019; DOI: 10.1158/1078-0432.CCR-19-0932

5

References:

1. Idbaih A, Canney M, Belin L, Desseaux C, Vignot A, Bouchoux G, et al. Safety and

Feasibility of Repeated and Transient Blood-Brain Barrier Disruption by Pulsed

Ultrasound in Patients with Recurrent Glioblastoma. Clin Cancer Res 2019 doi

10.1158/1078-0432.CCR-18-3643.

2. Carpentier A, Canney M, Vignot A, Reina V, Beccaria K, Horodyckid C, et al. Clinical trial

of blood-brain barrier disruption by pulsed ultrasound. Sci Transl Med 2016;8(343):343re2

doi 10.1126/scitranslmed.aaf6086.

3. McDannold N, Vykhodtseva N, Raymond S, Jolesz FA, Hynynen K. MRI-guided targeted

blood-brain barrier disruption with focused ultrasound: histological findings in rabbits.

Ultrasound Med Biol 2005;31(11):1527-37 doi 10.1016/j.ultrasmedbio.2005.07.010.

4. O'Reilly MA, Waspe AC, Chopra R, Hynynen K. MRI-guided disruption of the blood-brain

barrier using transcranial focused ultrasound in a rat model. J Vis Exp 2012(61) doi

10.3791/3555.

5. Treat LH, McDannold N, Zhang Y, Vykhodtseva N, Hynynen K. Improved anti-tumor

effect of liposomal doxorubicin after targeted blood-brain barrier disruption by MRI-guided

focused ultrasound in rat glioma. Ultrasound Med Biol 2012;38(10):1716-25 doi

10.1016/j.ultrasmedbio.2012.04.015.

Figure 1. Next steps in development of implantable ultrasound. Boxes represent

implantable ultrasound device.

Research. on November 9, 2020. © 2019 American Association for Cancerclincancerres.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 10, 2019; DOI: 10.1158/1078-0432.CCR-19-0932

6

Table: Ongoing early phase clinical trials investigating ultrasound for BBB opening

Device/Intervention Disease/ Population

phase No pts Location Status NCT#

Implantable US “Sonocloud-1” GBM rec 1 21 Paris, France

completed 02253212

Implantable US “Sonocloud-9” GBM rec 1 / 2 30 International completed 03744026

Transcranial MRI-guided focused ultrasound “Exablate”

GBM rec 1 10 Toronto, Canada

completed 02343991

Transcranial focused ultrasound “Navi”

GBM rec 1 9 Taoyuan, Taiwan

recruiting 03626896

Transcranial MRI-guided focused ultrasound “Exablate”

Breast ca mets

1 10 Toronto, Canada

planned 03714243

Transcranial MRI-guided focused ultrasound “Exablate”

High-grade glioma rec

1 20 Baltimore,

USA

recruiting 03551249

GBM; glioblastoma, mets; brain metastases, NCT#; registration number in clinicaltrials.gov

Rec; recurrent

Research. on November 9, 2020. © 2019 American Association for Cancerclincancerres.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 10, 2019; DOI: 10.1158/1078-0432.CCR-19-0932

© 2019 American Association for Cancer Research

MultipleUS probes

Large volumeof BBBdisruption

Implantableultrasound

Safe

Feasible

BBB disruption

Repeated treatments

Intraoperativepharmacokinetic

studies

Evidence ofelevated drugconcentrationin human brain

Safetyproof ofprinciple

E�cientregulatorypathway

Randomized trials

Exploringmultipledrugs

E�cacy and broad impact

Research. on November 9, 2020. © 2019 American Association for Cancerclincancerres.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 10, 2019; DOI: 10.1158/1078-0432.CCR-19-0932

Published OnlineFirst May 10, 2019.Clin Cancer Res   Adam M Sonabend and Roger Stupp  ultrasound deviceOvercoming the blood-brain barrier with an implantable

  Updated version

  10.1158/1078-0432.CCR-19-0932doi:

Access the most recent version of this article at:

  Manuscript

Authorbeen edited. Author manuscripts have been peer reviewed and accepted for publication but have not yet

   

   

   

  E-mail alerts related to this article or journal.Sign up to receive free email-alerts

  Subscriptions

Reprints and

  .pubs@aacr.orgDepartment at

To order reprints of this article or to subscribe to the journal, contact the AACR Publications

  Permissions

  Rightslink site. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC)

.http://clincancerres.aacrjournals.org/content/early/2019/05/10/1078-0432.CCR-19-0932To request permission to re-use all or part of this article, use this link

Research. on November 9, 2020. © 2019 American Association for Cancerclincancerres.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 10, 2019; DOI: 10.1158/1078-0432.CCR-19-0932